Advances in biochemistry and molecular biology have resulted identification and characterization of many therapeutic macromolecules, including, for example, growth hormone, erythropoietin, insulin, IGF, and the like. Administration of these molecules can result in drastic improvements in quality of life for subjects afflict with a wide range of ailments.
However, administration of these therapeutic macromolecules remains problematic. Currently, therapeutic macromolecules are typically administered by injection. Such injections require penetration of the subject's skin and tissues and are associated with pain. Further, penetration of the skin breaches one effective nonspecific mechanism of protection against infection, and thus can lead to potentially serious infection.
Previous attempts have been made for needleless delivery of macromolecules to subjects. See, e.g., International Patent Publication No. WO 01/30,392. In these efforts, delivery vehicles are used to deliver macromolecules to a subject through polarized epithelial cells. However, these derivatives lack a cleavable linker that is cleavable by an enzyme at the basal-lateral membrane of a polarized epithelial cell. Without cleavage, the probability of induction of an immune response against the delivery vehicle and/or the macromolecule to be delivered is increased. Also, steric hindrance between the delivery vehicle and the macromolecule can reduce the activity of the macromolecule, reducing efficacy of the treatment.
Accordingly, there is an unmet need for new methods and compositions that can be used to administer macromolecules to subjects without breaching the skin of the subject. This and other needs are met by the methods and compositions of the present invention.